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Ranajit Kumar Sutradhar1*
, Aongchainu Marma1
and Md. Emdad Hossain2
1Department of Chemistry, Chittagong University of Engineering and Technology, Chattogram, Bangladesh.
2Wazed Miah Science Research Center, Jahangirnagar University, Dhaka, Bangladesh.
Corresponding Author E-mail: rksutradhar2002@yahoo.com
Article Publishing History
Article Received on : 13 Jul2024
Article Accepted on : 02 Sep 2024
A new series of quinoline-thiazole compounds (1b-3b) were synthesized by two step reaction where thiosemicarbazone derivatives (1a-3a) were obtained from quinolinecarbaldehyde and thiosemicarbazide. The final products (1b-3b) were synthesized from thiosemicarbazone and 3-chloroacetylacetone. Characterizations of all synthesized compounds (1a-3a, 1b-3b) were performed by IR, Proton and Carbon-13 NMR spectroscopic methods. In vitro antimicrobial studies of thiazole derivatives (1b-3b) were screened by agar disc diffusion method. Compounds 1b and 3b revealed significant antibacterial effects against B. cereus, K. pneumonia, S. aureus and 2b revealed potential antibacterial effects against S. aureus, K. pneumonia with standard. Compounds 1b, 2b and 3b showed significant antifungal activities against the fungi A. niger with standard amphotericin B. In silico molecular docking studies performed by DFT method revealed that compound 1b and 3b showed good binding score against 2BTF protein taken from protein data bank.
KEYWORDS:Bioactivity; Molecular Docking; Thiazole Derivatives
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Copy the following to cite this article:Sutradhar R. K, Marma A, Hossain M. E. Synthesis, Bioactivity Screening and Docking Analysis of Thiazole Derivatives Containing Quinoline Moieties. Orient J Chem 2024;40(5).
Sutradhar R. K, Marma A, Hossain M. E. Synthesis, Bioactivity Screening and Docking Analysis of Thiazole Derivatives Containing Quinoline Moieties. Orient J Chem 2024;40(5). Available from: https://bit.ly/4hCLdHt
Introduction
Due to expansive and repeated uses of antibiotics, drug-resistant and multidrug resistant viral and bacterial infections are increasing in alarming rate that have brought out difficult to treat using previous antibiotic and take much time to cure1. Multidrug resistant grown up by accumulating multiple genes in bacteria and virus cell that code resistance to the drug or increasing the expression of genes coding for multidrug efflux2. This multidrug resistance caused by bacteria and virus accumulated genes drives the researchers to improve new and potential antibiotic agents to specific target. The synthesis of thiazole derivatives containing quinoline moieties is an attractive field in synthetic organic chemistry and therapeutic science. Thiazole moiety in natural products are found in vitamin B1 (thiamin), erythrazole B, firefly luciferin, marine natural products and other various compounds3-5. Thiazole and its derivatives exhibit wide range and important bioactivities i.e. antioxidant, antibacterial, anticancer, antifungal, anti-HIV, anti-inflammatory effects6-8. Having pharmacologically active properties most uses drugs contain thiazole moiety, for examples Sulfathiazol as antimicrobial drug9, Nitazoxanide as Antiparasitic Agent10, Ravuconazole as Anti-fungal11, Thiamethoxam as Insecticide12, Ritonavir as Anti-HIV13, Meloxicam as Antiinflammatory14 etc.
Another novel compounds, quinoline alkaloids extracted from natural products show observable and distinctive biological activities and due to its simple structure and their significant properties, researchers have great interest to extract or synthesize quinoline and its derivatives15. Quinoline alkaloids are observed and derived from many organism i.e. animals and plants16-17 those have numerous pharmacological and biological activities such as antibacterial effects against bacterial infections, antifungal effects against fungal infections, antitumor, anti-inflammatory, antioxidant, antiviral activities18.
The combination of two or more bioactive molecules i.e. thiazole and quinoline moiety in a molecular scaffold shows good antimicrobial activity19. Moreover, in the research, has been found that thiazole and quinoline moieties have minimum cytotoxicity to hepatocyte cells20.
Considering above biological significance as core structure of several drugs, a new series of thiazole derivatives containing quinoline moieties were synthesized and characterized. All synthesized quinoline thiazole derivatives were evaluated antibacterial and antifungal effects using agar disc diffusion method21. In these experiments, three gram-positive bacteria called B. cereus, S. aureus and B. magaterium, three gram-negative bacteriacalled K. pneumonia, E. coli and P. aeruginosa, two fungal strains called T. harzianum and A. niger were used.
Materials and Methods
Chemicals (Reagents)
All required chemicals to prepare thiazole derivatives containing quinoline moieties were purchased from the Merck and Sigma aldrich and used without purification.
Experimental
Melting points of quinoline-thiazole derivatives were recorded in melting points apparatus of Fisher John (Model no. 1A 9000) and uncorrected. Infrared spectrum was measured in KBr disk on Shimadzu FTIR spectrophotometer (Model FTIR- IR Affinity-1) and printed in cm-1. 1H-NMR, 13C-NMR, DEPT-135, COSY, HSQC and HMBC of the samples were performed by Bruker Advance-III HD spectrometer operated at 400 MHz and 100 MHz at Wazed Miah Scientific Research Centre, University of Jahangirnagar, Dhaka, Bangladesh. Chemical shifts (d) were recorded in ppm relative to TMS and J in Hz unit. Spin multiplicities were expressed as singlet (s), doublet (d), double doublet (dd), triplet (t), quartet (q) and multiplet (m).
Synthesis of Thiosemicarbazone
Synthesis of compounds (1a – 3a):
The thiosemicarbazide (3 mmol) and quinoline-carbaldehyde (3 mmol) were taken in a two neck flask with ethanol solvent and refluxed with stirring for eight hours at 78-80°C to obtain the thiosemicarbazone precipitate. Then it was kept in an ice-bath to cool down followed by filtration. The products were dried and weighed (Scheme-01).
Synthesis of compounds (1b – 3b)
3-chloroacetyleacetone (3 mmol) and thiosemicarbazone (3 mmol) were taken in a two neck flask with ethanol solvent and kept by stirring for 24 hours followed by refluxing for three hours at 58-60°C. Then it was cooled down and precipitate was separated by filtration followed by dried and weighed (Scheme-02).
Result and Discussion
Optimization of Reaction
Thiazole derivatives containing quinoline moieties were synthesized by two step reactions. In step-1 thiosemicarbazone derivatives were synthesized from quinoline-carbaldehyde and thiosemicarbazide in ethanol by refluxing for eight hours (Scheme 1). Then, the final products thiazole derivatives (1b-3b) were obtained from thiosemicarbazone derivatives and 3-chloroacetyleacetone by refluxing for three hours in acetone (Scheme 2). Characterizations of all synthesized compounds (1a-3a, 1b-3b) were performed by Infrared (IR), Proton (1H) NMR, Carbon-13 (13C) NMR, DEPT, COSY, HSQC and HMBC spectroscopic methods. Data obtained from the Scheme 1 and Scheme 2 reactions are given in the following Table 1.
Table 1: Compounds with yield (%) and time (hour)
Compounds
Colors
Texture
Time (hr)
Yield (%)
1a
Yellow
Cotton like solid
6
76%
2a
Yellow
Powder
5
70%
3a
Yellow
Powder
6
69%
1b
Reddish orange
Crystal
4
68%
2b
Reddish orange
Crystal
5
71%
3b
Brown
Powder
7
69%
Characterizations of compounds:
Compounds (1a – 3a) showed sharp absorptions at ῡmax cm-1 : 3439- 3392 (N-H stretching) and 1610-1602 (N-H bending) in IR spectra. Absorption bands at ῡmax 1278-1257, 1620-1615, 1610-1508 defined the presence of aromatic C=C, HC=N and C=S bonds respectively.
1H NMR spectra revealed that aromatic protons are present at δ ppm 8.94-7.61. Olifinic protons (H-C=N) appeared at δ 8.88-8.24. NH2 and NH protons appeared at δ 8.84-8.32 and 11.81-11.70 respectively. IR spectra of compounds (1b – 3b) showed absorption bands at ῡmax 1635-1616 for N-H bending and 3440- 3385 for N-H stretching and bands at ῡmax 1690- 1685 for C=O carbonyl functions. In 1H NMR, aromatic protons appeared at δ 9.04-7.20, olifinic protons (H-C=N) appeared at δ 8.92-8.35 and NH protons appeared at δ 12.16-11.85. Absorption peaks around at δ 2.55-2.50 due to COCH3 and singlet around at δ 2.46-2.42 for the methyl protons attached to carbon C4″. The structures of all synthesized thiosemicarbazone and thiazole derivatives compounds were further confirmed by 13C NMR and all the characteristic absorption values are shown in experimental data. Connectivity and correlations were confirmed by 2D COSY, HSQC and HMBC. The important correlations homo-nuclear (H-H) and hetero-nuclear (H-C) in HMBC are shown in Figure 1.
Biological Activity
Preparation of Media
In vitro antimicrobial effects of all the synthesized thiazole derivatives were tested by Agar disc diffusion method 21. Potato Dextrose and Mueller Hinton Agar (PDA & MHA) (HIMEDIA, India) media were taken as basal media for antimicrobial screening of experimental bacterial and fungal strains. In this method, the incubations of PDA and MHA were done for twenty four hours and then the contaminations were observed. After incubation, the bacterial and fungal strains were inoculated on media with sterile cotton bar. Then, the sample disc was put very carefully on agar medium that was pre-inoculated. The agar plates were aerobically incubated for twenty four hours at 37°C for antibacterial and for forty eight hours at 26°C for antifungal screening. The media were controlled by adding Dimethyl sulfoxide (DMSO). 25µL of sample solution in DMSO were added each disc that contain 300 µg of thiazole derivatives. 25µL of Ciprofloxacin and iconazole solution in DMSO was added on per disc as positive control of antibacterial and antifungal screening respectively. Finally, after 24 h incubation, the inhibition zone’s diameter was measured by circling the disc.
Antibacterial Activities Assay
Antibacterial screening of these newly synthesized thiazole compounds were observed exhibiting different activities against the selected bacteria. All the compounds were observed remarkable antibacterial activities with K. pneumonia, B. cereus, S. aureus and E. coli bacterial strains. Moreover, 1b revealed promising antibacterial effects against B. Cereus, K. pneumonia E. coli and S. aureus. 2b revealed significant activities against K. pneumonia and S. aureus and 3b revealed potential antibacterial effects against S. aureus and E. coli with standard Ampicillin. In the antibacterial study, the DMSO as control and ampicillin as standard have been studied for the comparison. The inhibition zones by different compounds are shown in the Table 2. The results are also shown by graphical representation in Figure 2.
Table 2: Results of antibacterial studies of the compounds 1b, 2b and 3b
Test
Samples
Zone of inhibitions in millimeter
Gram-positive bacteria
Gram-negative bacteria
Bacillus
cereus
Staphylococcus
aureus
Bacillus magaterium
Klebsiella
pneumonia
Pseudomonas aeruginosa
Escherichia
coli
1b
20
21
8
22
9
20
2b
16
24
0
24
7
22
3b
18
23
7
21
0
24
DMSO
0
0
0
0
0
0
Ampicillin
32
29
32
34
29
28
Antifungal Activities
The antifungal activities of newly prepared thiazole derivatives were observed inhibiting mycelial growth of experimental fungal strains. All the samples exhibited significant antifungal activities against the fungi A. niger. Moreover, compound 2b alsoshowed moderate antifungal activity against the fungi T. harzianum. Solvent DMSO and amphotericin B as standard have also been studies for the comparison. The inhibitions of mycelial growth by different test samples are shown in the Table 3 and also shown by a graphical representation in Figure 3.
Table 3: Antifungal activities of the compounds 1b, 2b and 3b
Test
Samples
% Inhibition of mycelialgrowth
Aspergillus niger
Trichoderma harzianum
1b
20
0
2b
16
15
3b
18
0
DMSO
0
0
Amphotericin B
23
24
Molecular Docking Studies
In silico docking studies were conducted to support the design of synthesized compounds and invention of new drug molecule for the effective inhibition of target protein of disease development. Docking studies of thiazole analogs were carried out by software package i.e. Gaussian 09, PyRx 0.8, and Pymol. Using Gaussian 09 version, structure optimizations of the synthesized thiazole analogs were performed on the basis of B3LYP/6- 31G (+, d, p) in the DFT method. Further, analyzing the docking results and calculating nonbonding interaction, Biovia Discovery Studio 4.1 was used. When docked against 2BTF, compound 1b and 3b showed binding score of -7.6 Kcal/mole and -7.9 Kcal/mole respectively. Interaction types and docking results are showed Figure 5 and Figure 6.
Table 4: Docking score and interaction type of compound 1b
Sample
Binding affinity (kcal/mol)
Residue in contact
Interaction types
Bond distance (Å)
1b
-7.6
ASP157
AC
5.27822
GLU214
AC
4.83023
ASP157
AC
4.40079
GLU214
AC
4.44543
GLY156
CHB
2.14822
GLY302
CHB
2.78748
MET305
Pi- A
4.71525
Figure 5: Molecular docking studies of 1b against receptor 2BTF. (A) 3D docking predictions. (B) 2D interaction sketches.
Table 5: Docking score and interaction type of compound 3b
Sample
Binding affinity (kcal/mol)
Residue in contact
Interaction types
Bond distance (Å)
3b
-7.9
PHE375
Salt Bridge AC
2.92903
PHE375
AC
5.57027
TYR133
CHB
2.16462
LYS373
CHB
2.53984
MET355
CH bond
2.59947
LYS373
CH bond
2.88734
ALA135
Pi-A
4.9566
VAL139
Pi-A
4.70596
LEU140
Pi-A
5.41948
LEU346
Pi-A
4.14628
AC = Attractive charge, CH bond = Carbon Hydrogen bond, CHB = Conventional hydrogen bond, Pi-A = Pi- Alkyl
Figure 6: Molecular docking studies of 3b against receptor 2BTF. (A) 3D docking predictions. (B) 2D interaction sketches.
In silico ADMET Prediction
Pharmacokinetic properties of synthesized thiazole compounds were studied by In silico ADMET Prediction method. Absorption, distribution, metabolism and excretion are the four steps of pharmacokinetic properties. Toxicity studies are also performed as a part of pharmacokinetic properties where acronym stands ADMET prediction 22.
The ADMET predictions of synthesized thiazole compounds were determined by ADMET online tool (www.swissadme.ch). The determined molecular properties and pharmacokinetic properties are summarized in Table 6 and Table 7.
Table 6: Molecular properties of synthesized thiazole derivatives
Name
Molecular Weight
LogP
Rotatable H-Bonds
H-Bonds Acceptors
H-Bonds Donors
Surface Area
1b
310.382
3.64832
4
6
1
131.286
2b
310.382
3.64832
4
6
1
131.286
3b
344.827
4.30172
4
6
1
141.590
Ampicillin
349.412
0.3181
4
5
3
143.121
Table 7: Pharmacokinetic Properties: ADMET Prediction
Name
Water
Solubility
(log mol/L)
HIA
(%Absorbed)
P-GI I inhibitor
BBB
(log BB)
CNS
(log PS)
hERG I inhibitor
hERG II inhibitor
ORAT (LD50)
(mol/kg)
1b
-4.038
93.099
No
0.168
-2.078
No
Yes
2.407
2b
-3.974
92.875
No
0.295
-2.112
No
Yes
2.417
3b
– 5.018
91.204
Yes
0.202
-1.949
No
Yes
2.358
Ampicillin
-2.396
43.034
No
-0.767
-3.166
No
No
1.637
HIA= Human intestinal absorption, BBB = Blood brain barrier, ORAT = oral Rat acute toxicity, CNS=Central nerve system, P-GI= P-glycoprotein inhibitor, hERG = human Ether-a- go-go Related Gene
Conclusion
Schiff base derivatives and their complexes are the most significant and valuable compounds which have many useful applications because of their chemical versatility. Most of the Schiff base thiazole compounds were used as active medicinal agents. As a consequence, the study focused on the synthesis and characterization of new thiosemicarbazones, thiazole derivatives containing quinolone moieties and screening their antibacterial and antifungal activities. First step syntheses compounds 1a, 2a and 3a; thiosemicarbazone derivatives and second step syntheses 1b, 2b and 3b thiazole derivatives compounds were characterized by Infrared, Proton-NMR, Carbon-13 NMR, DEPT, COSY, HSQC and HMBC spectroscopy. It was visualized that compounds 1b and 3b significantly exhibited antibacterial and antifungal activities. In the docking studies, compounds 1b and 3b showed binding score of -7.6 Kcal/mole and -7.9 Kcal/mole respectively.
Acknowledgement
The authors are highly thanked to the Ministry of Science and Technology, Peoples Republic of Bangladesh for providing financial assistance to accomplish this research work.
Funding Sources
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
The author(s) do not have any conflict of interest.
Data Availability Statement
This statement does not apply to this article.
Ethics Statement
This research did not involve human participants, animal subjects, or any material that requires ethical approval.
References
Shankar, P.R.; Balasubramanium, R.; WHO, 2014, Antimicrobial resi.: glo. rep. on surve.Nikaido; Hiroshi; Annual review of biochemistry 2009, 78, 119-46.
This work is licensed under a Creative Commons Attribution 4.0 International License.
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